The development of congestive heart failure (CHF) is associated with left ventricular (LV) dilation and myocardial remodeling. However, fundamental mechanisms that contribute to this remodeling process with the progression of CHF remain unclear. The matrix metalloproteinases (MMPs) have been demonstrated to play a significant role in tissue remodeling in a number of pathological processes. The present project tested the hypothesis that the LV dilation and remodeling during the progression of CHF is associated with early changes in MMP expression and zymographic activity. LV and myocyte function, collagen content, and MMP expression and zymographic activity were serially measured during the progression of CHF caused by pacing-induced supraventricular tachycardia (SVT) in pigs. After 7 days of SVT, LV end-diastolic dimension and myocyte length both increased by 15% from control values, and LV fractional shortening fell by 20%. At the level of the myocyte, percent shortening fell by 16% after 7 days of SVT, with no change in the steady-state velocity of shortening. Longer durations of SVT caused progressive LV dilation, LV pump failure, and myocyte contractile dysfunction. Specifically, 21 days of SVT resulted in a >50% increase in LV dimension, a 56% fall in LV fractional shortening, and a 33% decline in myocyte velocity of shortening. The decline in LV and myocyte function with 21 days of SVT was accompanied by signs and symptoms of CHF. Thus, SVT causes time-dependent changes in LV geometry and function and the subsequent development of CHF. LV myocardial collagen content and confluence fell by >25% after 7 days of SVT and were accompanied by an 80% increase in LV myocardial MMP zymographic activity against the substrate gelatin. After 14 days of SVT, total LV myocardial collagen content was reduced by 24%, and LV myocardial MMP zymographic activity increased by >100% from control values. Interstitial collagenase (MMP-1), stromelysin (MMP-3), and 72-kD gelatinase (MMP-2) were increased by approximately 2-fold after 7 days of SVT. LV MMP zymographic activity and abundance remained elevated with longer durations of SVT. The results of the present study demonstrated that in this model of CHF, early changes in LV myocardial MMP zymographic activity and protein levels occurred with the initiation and progression of LV dilation and dysfunction. These findings suggest that an early contributory mechanism for the initiation of LV remodeling that occurred in this model of developing CHF is enhanced expression and potentially increased activity of LV myocardial MMPs.
These findings suggest that the effects of ACEI in the setting of CHF are not solely due to modulation of Ang II levels but rather to alternative enzymatic pathways and that combined ACEI and AT1 Ang II receptor blockade may provide unique benefits for LV pump function and neurohormonal systems in the setting of CHF.
Increased plasma concentrations of endothelin have been identified in patients and animals with severe congestive heart failure (CHF). However, whether and to what extent increased endothelin (ET) concentrations influence left ventricular (LV) myocyte contractility, ET-receptor subtype density, and endogenous ET production with the development of CHF remains unclear. Accordingly, myocyte contractile function, response to ET, sarcolemmal ET-receptor density, and myocyte ET production were examined in pigs following the development of pacing-induced CHF (240 beats/min, 3 wk, n = 8) and in controls (n = 8). With CHF, plasma ET increased over threefold. In the presence of ET (10-500 pM), myocyte contractility increased in a dose-dependent manner in control myocytes but decreased in CHF myocytes. For example, in the presence of 200 pM ET, velocity of shortening increased by 32.8 +/- 2.3 microns/s in controls but decreased by 8.3 +/- 2.2 microns/s with CHF. LV sarcolemmal ET-receptor density was primarily of the ETA-receptor subtype in controls (96 +/- 1.0%) and was unchanged with CHF. In quiescent myocyte preparations, control myocytes secreted ET (2.29 +/- 0.45 amol.cell-1.h-1), which was similar in CHF myocytes. These findings suggest that the production of ET may have important and potentially differential effects on contractile function with the development of CHF.
The unique findings of this study were twofold. First, basic defects in specific components of the myocyte excitation-contraction coupling process that occur with CHF are reversible. Second, combined ACEI and AT1 Ang II blockade may provide unique benefits on myocyte contractile processes in the setting of CHF.
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